UPLC (R)-RAD the new standard in quality control of PET radiopharmaceuticals

Objectives: Good Manufacturing Practice (GMP) compliant productions require validated, quality control procedures of the radiopharmaceutical. Quality control of the final product is conventionally performed by High Performance Liquid Chromatography (HPLC) with UV and radioactivity (RAD) detection. To use an ACQUITY Ultra Performance Liquid Chromatography (UPLC®) with an online UV and RAD detector we improved not only the analysis time, but also linearity, resolution, reproducibility, precision, accuracy, signal-to-noise ratio, limit of quantitation (LOQ) and limit of detection (LOD) compared to conventional HPLC quality control analysis. Materials and Methods: A Waters H-class UPLc® with a variable UV detector and an online Berthold flowstar LB 513 radioactivity detector was used to measure the (radioactive) concentrations of the radiopharmaceutical and impurities in the samples. The UPLc® columns used were from the Waters ACQUITY UPLC® line, with a 2.1 or 3.0 mm i.d. by 50 mm length and a particle size of 1.7μm Flow rates can vary from 0.4 till 1.0 ml/min dependent on the procedure. Total run time of a quality control method is 2-3 minutes. Aliquots from 1-10 μL are needed for quality control. To validated new UPLC® analysis Methods we performed a full validation (PQ). As part of the validation of the new UPLC® Methods we performed a comparison with the conventional HPLC Methods. PET radiopharmaceuticals; such as fluorine-18 labeled FLT, FAZA, FDOPA, FES and carbon-11 labeled PK11195, PIB, 5-HTP and methionine were used in this study. Results: Due to shorter conditioning-run- and rinse times, the solvents cost reduced up to 80% significantly. The higher resolution and lower LOQ gave a better and more accurate result of the concentration of compounds. Both for the UV and radioactivity signal, the measurability of impurities possible present in the production sample is considerably increased. Indeed, more impurities are detected. However, the total amounts of these impurities are far below the release criteria of 1 mg. L-1. Radioactivity concentrations > 0.3 MBq/ml could reliably be measured with the Berthold RAD detector. Conclusion: The UPLC®-RAD gave better linearity, reproducibility, sensitivity and higher resolution then conventional HPLC with UV/RAD detection. Especially for the11C radiopharmaceuticals, a reduction in the analysis time of 12 min leads to 34% more released radioactivity, ready for injection. For18F-radiopharmaceuticals the profit is still 7%. Thus, UPLc®-RAD might become the new standard in quality control of PET radiopharmaceuticals.